Sandbox Reserved 193: Difference between revisions

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== Mutations in palmitoyl thiosterase 1==

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== INCL ==

Various mutations have been found in INCL patients ( Hofmann S L, Das A K, Yi W, Lu J-Y, Wisniewski K E. Mol Genet Metab. 1999;66:234–239. [PubMed]Das A K, Becerra C H R, Yi W, Lu J-Y, Siakotos A N, Wisniewski K N, Hofmann S L. J Clin Invest. 1998;102:361–370. [PMC free article] [PubMed]). Most of these mutations are caused by nonsense or missense mutations within close proximity to the catalytic triad. These mutations lead to an inactive PPT1 enzyme as they are predicted to create unfavorable steric, polar, and electrostatic interactions that could disturb the nucleophilic elbow. The nucleophilic elbow is responsible for proper location and orientation of the Ser 115 (part of the catalytic triad link?). Catalytic ability would be greatly reduced if the original position of Ser115 was altered because it must be properly orientated to be activated by His289 (part of the catalytic triad Link?) in order to attack the substrate. One example of mutation such as <scene name='58/580837/Methionine/2'>Val181Met</scene> and <scene name='58/580837/Lysine_mutation/2'>Glu184Lys ~~Mutated~~</scene> give a good depiction of how the increase in size in the mutated amino acids and positive charge on lysine mutation would create steric and polar clashes with the adjacent helices of the binding pocket compared to the <scene name='58/580837/Val181glu184/2'>Normal Val181 & Glu184</scene> <scene name='58/580837/Arginine_fine/2'>Arg122</scene> is described in more detail below.

Various mutations have been found in INCL patients ( Hofmann S L, Das A K, Yi W, Lu J-Y, Wisniewski K E. Mol Genet Metab. 1999;66:234–239. [PubMed]Das A K, Becerra C H R, Yi W, Lu J-Y, Siakotos A N, Wisniewski K N, Hofmann S L. J Clin Invest. 1998;102:361–370. [PMC free article] [PubMed]). Most of these mutations are caused by nonsense or missense mutations within close proximity to the catalytic triad. These mutations lead to an inactive PPT1 enzyme as they are predicted to create unfavorable steric, polar, and electrostatic interactions that could disturb the nucleophilic elbow. The nucleophilic elbow is responsible for proper location and orientation of the Ser 115 (part of the catalytic triad link?). Catalytic ability would be greatly reduced if the original position of Ser115 was altered because it must be properly orientated to be activated by His289 (part of the catalytic triad Link?) in order to attack the substrate. One example of mutation such as <scene name='58/580837/Methionine/2'>Val181Met</scene> and <scene name='58/580837/Lysine_mutation/2'>Glu184Lys</scene> give a good depiction of how the increase in size in the mutated amino acids and positive charge on lysine mutation would create steric and polar clashes with the adjacent helices of the binding pocket compared to the <scene name='58/580837/Val181glu184/2'>Normal Val181 & Glu184</scene> <scene name='58/580837/Arginine_fine/2'>Normal Arg122</scene> is described in more detail below.

Known INCL Mutations

Sandbox Reserved 193: Difference between revisions

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 == Mutations in palmitoyl thiosterase 1==
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 == INCL ==
-Various mutations have been found in INCL patients ( Hofmann S L, Das A K, Yi W, Lu J-Y, Wisniewski K E. Mol Genet Metab. 1999;66:234–239. [PubMed]Das A K, Becerra C H R, Yi W, Lu J-Y, Siakotos A N, Wisniewski K N, Hofmann S L. J Clin Invest. 1998;102:361–370. [PMC free article] [PubMed]). Most of these mutations are caused by nonsense or missense mutations within close proximity to the catalytic triad. These mutations lead to an inactive PPT1 enzyme as they are predicted to create unfavorable steric, polar, and electrostatic interactions that could disturb the nucleophilic elbow. The nucleophilic elbow is responsible for proper location and orientation of the Ser 115 (part of the catalytic triad link?). Catalytic ability would be greatly reduced if the original position of Ser115 was altered because it must be properly orientated to be activated by His289 (part of the catalytic triad Link?) in order to attack the substrate. One example of mutation such as <scene name='58/580837/Methionine/2'>Val181Met</scene> and <scene name='58/580837/Lysine_mutation/2'>Glu184Lys Mutated</scene> give a good depiction of how the increase in size in the mutated amino acids and positive charge on lysine mutation would create steric and polar clashes with the adjacent helices of the binding pocket compared to the <scene name='58/580837/Val181glu184/2'>Normal Val181 & Glu184</scene>  <scene name='58/580837/Arginine_fine/2'>Arg122</scene> is described in more detail below.
+Various mutations have been found in INCL patients ( Hofmann S L, Das A K, Yi W, Lu J-Y, Wisniewski K E. Mol Genet Metab. 1999;66:234–239. [PubMed]Das A K, Becerra C H R, Yi W, Lu J-Y, Siakotos A N, Wisniewski K N, Hofmann S L. J Clin Invest. 1998;102:361–370. [PMC free article] [PubMed]). Most of these mutations are caused by nonsense or missense mutations within close proximity to the catalytic triad. These mutations lead to an inactive PPT1 enzyme as they are predicted to create unfavorable steric, polar, and electrostatic interactions that could disturb the nucleophilic elbow. The nucleophilic elbow is responsible for proper location and orientation of the Ser 115 (part of the catalytic triad link?). Catalytic ability would be greatly reduced if the original position of Ser115 was altered because it must be properly orientated to be activated by His289 (part of the catalytic triad Link?) in order to attack the substrate. One example of mutation such as <scene name='58/580837/Methionine/2'>Val181Met</scene> and <scene name='58/580837/Lysine_mutation/2'>Glu184Lys</scene> give a good depiction of how the increase in size in the mutated amino acids and positive charge on lysine mutation would create steric and polar clashes with the adjacent helices of the binding pocket compared to the <scene name='58/580837/Val181glu184/2'>Normal Val181 & Glu184</scene>  <scene name='58/580837/Arginine_fine/2'>Normal Arg122</scene> is described in more detail below.
 Known INCL Mutations